Oncotarget

Research Papers:

TREM-2 serves as a negative immune regulator through Syk pathway in an IL-10 dependent manner in lung cancer

Yinan Yao _, Hequan Li, Junjun Chen, Weiyi Xu, Guangdie Yang, Zhang Bao, Dajing Xia, Guohua Lu, Shuwen Hu and Jianying Zhou

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Oncotarget. 2016; 7:29620-29634. https://doi.org/10.18632/oncotarget.8813

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Abstract

Yinan Yao1,*, Hequan Li1,*, Junjun Chen1, Weiyi Xu2, Guangdie Yang1, Zhang Bao1, Dajing Xia3,4, Guohua Lu1, Shuwen Hu1, Jianying Zhou1

1Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China

2Department of Clinical Laboratory, First Affiliated Hospital of Zhejiang University, Hangzhou, China

3School of Public Health, Zhejiang University, Institute of Immunology, Zhejiang University, Hangzhou, China

4Institute of Immunology, Zhejiang University, Hangzhou, China

*These authors have contributed equally to this work

Correspondence to:

Jianying Zhou, email: zjyhz@zju.edu.cn

Hequan Li, email: lihequan@zju.edu.cn

Keywords: TREM-2, lung cancer, IL-10, Syk, immunoregulation

Received: October 20, 2015    Accepted: March 28, 2016    Published: April 18, 2016

ABSTRACT

During infection, triggering receptor expressed on myeloid cells-2 (TREM-2) restrains dendritic cells (DCs) and macrophages (MΦs) phagocytosis, as well as reduces pro-inflammatory cytokines release through DNAX-activation protein 12 (DAP12) signaling. However, the role of TREM-2 signaling in cancer has never been elucidated. In the current study, we found that TREM-2 was up-regulated on peripheral blood monocytes in tumor-bearing host. More TREM-2+DCs were detected in the lung of 3LL tumor-bearing mice. On the other hand, the level of TREM-2 on pulmonary MΦs positively correlated with the pathological staging of lung cancer. However, surgical or chemotherapeutic reduction of tumor burden led to the obvious decline of TREM-2. In vitro, TREM-2 expression of bone marrow (BM)-derived DCs and MΦs was induced by conditional medium (CM) containing the supernatant of 3LL cells. TREM-2+DCs from CM and/or tumor-bearing mice held altered phenotypes (CD80LowCD86LowMHCIILow) and impaired functions, such as, reduced interleukin (IL)-12 secretion, increased IL-10 production, and weakened ovalbumin (OVA)-endocytic capacity; also developed potent inhibitory effect on T cell proliferation that could be partially reversed by TREM-2 blockage. Moreover, spleen tyrosine kinase (Syk) inhibitor restrained IL-10 production of TREM-2+DC. Remarkably, IL-10 neutralizing antibody and Syk inhibitor both lowered the suppressive potential of TREM-2+DCs in T cell proliferation. Also, adoptive transfer of this TREM-2+DCs accelerated the tumor growth rather than jeopardized survival in lung cancer-bearing mice. In conclusion, these results indicate that TREM-2 might act as a negative immuno-regulatory molecule through Syk pathway in an IL-10 dependent manner and partially predicts prognosis in lung cancer patients.


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